Perfluoro-1-azatricyclic amine compound

ABSTRACT

A novel compound of the formula, ##STR1## wherein k is zero or an integer of 1 to 2, j is an integer of from 1 to 3, l and m are each zero or an integer of from 1 to 3, and n is an integer of from 1 to 4, the rings A, B and C being optionally substituted with at least one trifluoromethyl group or tetrafluoroethyl group is prepared by reacting the perhydro compound corresponding thereto with fluorine. The compound is useful as a material capable of carrying oxygen in an aqueous emulsion for lifesaving a patient suffering from massive hemorrhage and for preserving internal organs in transplantation.

This invention relates to a novel perfluorotricyclic amine compounduseful as an oxygen carrier in an artificial blood or in an infusionfluid.

More particularly, it relates to a perfluoro-1-azatricyclic aminecompound represented by the general formula ##STR2## wherein k is zeroor an integer of 1 or 2, j is an integer of from 1 to 3, l and m areeach zero or an integer of from 1 to 3, and n is an integer of from 1 to4, the rings A, B and C being optionally substituted with at least onetrifluoromethyl or pentafluoroethyl group.

Regarding the general formula (I), it is preferable that the ring A isselected from five- to eight-membered rings, the ring B from five- toeight-membered rings, and the ring C from five- to eight-membered rings.The total number of the carbon atoms contained in the compound offormula (I) is preferably from 9 to 12.

In detail, the first series of the present perfluoro-1-azatricyclicamine compounds without optional substituent of --CF₃ or --C₂ F₅ isrepresented by the formula, ##STR3##

The compound of the above formula may have the substituent(s), and thepreferable total number of the compound being 9 to 11.

The second series is also represented by the formula, ##STR4## whereink, j, l, m and n are each zero or an integer of 1 or 2; provided that kand j are not simultaneously zero nor more than 2.

The compound may have one trifluoromethyl group as substituent and itstotal number of carbon atoms is preferably 10 to 12 in case of nosubstituent and 11 in case of the presence of the substituent.

The third series is also represented by the formula, ##STR5## wherein n,l and m are each zero or an integer of from 1 to 3, provided that anyone of the l, m and n is an integer of from 1 to 3.

The compound may have one trifluoromethyl group as substituent and itstotal number of carbon atoms is preferably 10 to 12 in case of nosubstituent and 11 in case of the presence of the substituent.

The compound of formula (I) can be prepared by fluorinating aperhydro-compound corresponding to the compound of formula (I). Themethods of fluorination include, for example, a direct fluorination, afluorination by use of cobalt trifluoride, and an electro chemicalfluorination.

The preparation of the compound of formula (I) of this invention ispreferably performed by the electrochemical fluorination method. This isperformed, for example, by mixing anhydrous hydrogen fluoride and theperhydro-compound used as the starting compound in an electrolytic celland subjecting the resulting solution of electrolysis. The voltage, thecurrent density at the anode, and the temperature of electrolyticsolution are normally 3-8 V, 0.1-3 A/dm² and 4°-12° C., respectively.

The compound of formula (I) thus formed was drained from the bottom ofthe cell, being insoluble in anhydrous hydrogen fluoride.

The isolation and purification of the compound from the drained productare carried out, for example, by adding a mixture of equal volumes of anaqueous caustic alkaline solution and an amine compound to the drainedproduct and refluxing to decompose partially fluorinated compounds.After cooled, the lowermost layer containing the desired compound offormula (I) is separated, washed with an aqueous acetone solutioncontaining a suitable amount of potassium iodide to removeperfluoroalkyl nitrogen fluorides, and subjected to fractionaldistillation to obtain the fraction of the desired compound of formula(I).

Since the compound of the formula (I) of this invention can not onlydissolve a large amount of oxygen, and is chemically and biologicallyinert, but also it can be excreted rapidly from the body, it can form,for example, an aqueous emulsion containing 5 to 50, preferably 10-40,%(W/V) of the compound of formula (I) to be used as an oxygen carrier inan artificial blood or in an infusion liquid for men and other mammalssuch as dogs, cats, cattle, mice, rats and guinea pigs.

The symbol "%(W/V)" referred to herein mean the amount of the materialby weight (gram) based on 100 ml of the resulting emulsion.

In the preparation of the emulsion mentioned above, there used, as anemulsifier, a nonionic surfactant and/or phospholipids in an addedamount of 1 to 5% (W/V).

As the medium for the emulsion, a physiologically acceptable aqueoussolution is employed. If necessary, there may be added thereto suchmaterials as glycerol to provide the desired isotonicity, and suchplasma expanders as HES or dextran to regulate the colloid osmoticpressure of the emulsion.

The emulsion can be prepared by mixing the above-mentioned ingredientsand homogenizing the mixture by means of, for example, a high-pressurejet type homogenizer until the particle diameters become 0.05 to 0.3 μm,preferably less than 0.2 μm.

The perhydro-compounds (starting compounds) corresponding to thecompounds of formula (I) are substantially known already.

EXAMPLE 1

Into an electrolytic cell made of Monel metal with an inner volume of1.5 l, which is provided with electrode plates (six plates as anode andseven plates as cathode) made of nickel (purity: 99.6% or higher)arranged alternately with an inter-electrode distance of 1.7-2.0 mm, theeffective anode surface area being 10.5 dm², and with a reflux condensermade of copper at the upper part of the cell, was introduced 1.2 l ofanhydrous hydrogen fluoride, and trace amounts of impurities present inthe system (moisture and sulfuric acid) were removed by preliminaryelectrolysis. Then, 1.0 mol (137 g) of 1-azatricyclo[5,2,1,0²,6 ]decanewas dissolved into the anhydrous hydrogen fluoride, and electrolysis wascarried out, while introducing helium gas from the bottom of the cell ata rate of 100 ml/min., under the conditions of anode current density of0.4-2.0 A/dm², voltage of 5-9 V and solution temperature 7°-12° C.,until the ampere-hours amounted to 900. Hydrogen fluoride was added at arate of 250 ml per 24 hours during the electrolysis. No attempt was madeto collect volatile products formed by a bond breaking reaction, whichwould give more yields of the desired product. After completion of theelectrolysis, fluorocarbons in the lower layer in the cell was drainedthrough the bottom of the cell, weighed 252 g (58% yield).

To the fluorocarbons thus separated, were added equal volumes of 70%aqueous potassium hydroxide solution and diisobutylamine, and theresulting mixture was refluxed for about five days. The reaction mixturewas then cooled in an ice bath, and filtered by suction. Theperfluoro-compounds sedimented in the lowermost layer were separated ina separatory funnel, washed successively with diluted sulfuric acid,concentrated sulfuric acid, saturated aqueous sodium hydrogen carbonatesolution, 90% aqueous acetone solution containing 3% of potassiumiodide, and water to yield 110 g of a transparent perfluoro-compound.The thus obtained perfluoro-compound free from contaminants containingprotons was distilled on a fractional distillation apparatus equippedwith a spinning band column to afford 33 g (7% yield) of the desiredproduct boiling at 120°-130° C. This product was collected, purified,and then analyzed by infrared absorption spectrometry, ¹⁹ F-nuclearmagnetic resonance spectrometory and mass spectrometory, and wasconfirmed to be the objective compound,perfluoro-1-azatricyclo[5,2,1,0²,6 ]decane of which chemical structurewas shown in Table 1 as compound No. 1.

EXAMPLES 2-26

A series of other perfluoro-1-azatricyclic amine compounds having theformula (II) and (IV) was synthesized from the correspondingperhydro-1-azatricyclic amine compounds and purified in the same manneras that described above and each product was confirmed to be theobjective compound upon analysis by infrared absorption spectrometory,¹⁹ F-nuclear magnetic resonance spectrometory and mass spectrometory.

The structural formula and the boiling point of each of the objectivecompounds and starting compounds are shown in Table 1. The symbol "F-"in the structural formula indicates that the compound is perfluorinated.For example, the formula ##STR6## indicates in its exact meaning theformula ##STR7##

                  TABLE 1                                                         ______________________________________                                        Ex-                                   Boil-                                   am-                                   ing                                     ple  Starting       Objective         pt.                                     No.  compound       compound          (°C.)                            ______________________________________                                        1    1-Azatricyclo [5,2,1,0.sup.2,6 ]decane                                                                         120- 130                                2    3-Methyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                             ##STR8##         143- 154                                3    4-Methyl-1-azatricyclo [5,2,1,0.sup.2,6 ]decane                                               ##STR9##         143- 153                                4    5-Methyl-1-azatricyclo [5,2,1,0.sup.2,6 ]decane                                               ##STR10##        143- 153                                5    8-Methyl-1-azatricyclo [5,2,1,0.sup.2,6 ]decane                                               ##STR11##        143- 153                                6    9-Methyl-1-azatricyclo [5,2,1,0.sup.2,6 ]decane                                               ##STR12##        143- 153                                7    10-Methyl-azatri- cyclo[5,2,1,0.sup.2,6 ]decane                                               ##STR13##        143- 154                                8    3-Ethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ]decane                                               ##STR14##        157- 168                                9    4-Ethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                              ##STR15##        156- 168                                10   5-Ethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                              ##STR16##        157- 168                                11   8-Ethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                              ##STR17##        157- 168                                12   9-Ethyl-1-azatri- cyclo[5,2,1,0.sup. 2,6 ] decane                                             ##STR18##        157- 168                                13   10-Ethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                             ##STR19##        158- 168                                14   3,4-Dimethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR20##        157- 168                                15   3,5-Dimethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR21##        158- 168                                16   3,8-Dimethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR22##        158- 168                                17   3,9-Dimethyl-1-azatri- cyclo[5,2,1,0.sup.2,6 ]decane                                          ##STR23##        158- 167                                18   3,10-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                        ##STR24##        157- 168                                19   4,5-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR25##        157- 168                                20   4,8-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR26##        157- 167                                21   4,9-Dimethyl-1- azatricyclo [5,2,1,0.sup.2,6 ]decane                                          ##STR27##        157- 168                                22   4,10-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                        ##STR28##        157- 167                                23   5,8-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ]  decane                                        ##STR29##        157- 167                                24   5,9-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR30##        157- 168                                25   5,10-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                        ##STR31##        157- 167                                26   8,9-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                         ##STR32##        158- 167                                27   8,10-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                        ##STR33##        157- 168                                28   9,10-Dimethyl-1-aza- tricyclo[5,2,1,0.sup.2,6 ] decane                                        ##STR34##        157- 167                                29   1-Azatricyclo [6,2,1,0.sup.2,7 ]undecane                                                      ##STR35##        143- 153                                30   3-methyl-1-azatricyclo [6,2,1,0.sup.2,7 ]undecane                                             ##STR36##        156- 167                                31   4-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,7 ] undecane                                           ##STR37##        157- 166                                32   5-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,7 ] undecane                                           ##STR38##        157- 166                                33   6-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,7 ] undecane                                           ##STR39##        156- 166                                34   9-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,7 ] undecane                                           ##STR40##        156- 166                                35   10-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,7 ] undecane                                          ##STR41##        156- 166                                36   11-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,7 ] undecane                                          ##STR42##        156- 166                                37   1-Azatricyclo [6,2,1,0.sup.2,6 ]undecane                                                      ##STR43##        143- 154                                38   3-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                           ##STR44##        156- 166                                39   4-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                           ##STR45##        156- 167                                40   5-methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                           ##STR46##        156- 167                                41   7-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                           ##STR47##        156- 167                                42   9-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                           ##STR48##        156- 166                                43   10-Methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                          ##STR49##        156- 167                                44   11-methyl-1-azatri- cyclo[6,2,1,0.sup.2,6 ] undecane                                          ##STR50##        156- 168                                45   1-Azatricyclo [6,2,1,0.sup.3,7 ]undecane                                                      ##STR51##        145- 154                                46   2-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                           ##STR52##        156- 168                                47   4-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                           ##STR53##        156- 167                                48   5-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                           ##STR54##        156- 167                                49   6-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                           ##STR55##        156- 166                                50   9-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                           ##STR56##        157- 167                                51   10-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                          ##STR57##        157- 167                                52   11-Methyl-1-azatri- cyclo[6,2,1,0.sup.3,7 ] undecane                                          ##STR58##        156- 167                                53   1-Azatricyclo [7,2,1,0.sup.2,6 ]dodecane                                                      ##STR59##        156- 166                                54   1-Azatricyclo [7,2,1,0.sup.2,7 ]dodecane                                                      ##STR60##        156- 167                                55   1-Azatricyclo [7,2,1,0.sup.2,8 ]dodecane                                                      ##STR61##        156- 166                                56   1-Azatricyclo [7,2,1,0.sup.3,7 ]dodecane                                                      ##STR62##        155- 165                                57   1-Azatricyclo [7,2,1,0.sup.3,8 ]dodecane                                                      ##STR63##        156- 166                                58   1-azatricyclo [7,2,1,0.sup.4,8 ]dodecane                                                      ##STR64##        155- 166                                59   1-Azatricyclo [8,2,1,0.sup.2,6 ]tridecane                                                     ##STR65##        158- 177                                60   1-Azatricyclo [8,2,1,0.sup.2,7 ]tridecane                                                     ##STR66##        167- 177                                61   1-Azatricyclo [8,2,1,0.sup.2,8 ]tridecane                                                     ##STR67##        167- 178                                62   1-Azatricyclo [8,2,1,0.sup.2.9 ]tridecane                                                     ##STR68##        166- 178                                63   1-Azatricyclo [8,2,1,0.sup.3,7 ]tridecane                                                     ##STR69##        167- 178                                64   1-Azatricyclo [8,2,1,0.sup.3,7 ]tridecane                                                     ##STR70##        166- 177                                65   1-Azatricyclo [8,2,1,0.sup.3,9 ]tridecane                                                     ##STR71##        167- 177                                66   1-Azatricyclo [8,2,1,0.sup.4,8 ]tridecane                                                     ##STR72##        167- 178                                67   1-Azatricyclo [8,2,1,0.sup.4,9 ]tridecane                                                     ##STR73##        167- 177                                68   1-Azatricyclo [8,2,1,0.sup.5,9 ]tridecane                                                     ##STR74##        166- 176                                ______________________________________                                    

EXAMPLES 69-107

A series of perfluorotricyclic amine compounds of the formula III wassynthesized, purified and confirmed to be the objective compound in thesame manner as in Example 1.

The structural formula and the boiling point of each of the objectivecompounds is shown in Table 2. The symbol "F-" in the structural formulaindicates that the compound is perfluorinated. For example, the formula##STR75## indicates in its exact meaning the formula ##STR76##

                  TABLE 2                                                         ______________________________________                                        Ex-                                                                           am-              Formula of                                                   ple  Starting    objective          Boiling                                   No.  compound    compound           pt. (°C.)                          ______________________________________                                        69   1-Azatricyclo [5,3,1,0.sup.2,6 ] undecane                                                                    143-152                                   70   3-Methyl-1- azatricyclo [5,3,1,0.sup.2,6 ] undecane                                        ##STR77##         156-167                                   71   4-Methyl-1- azatricyclo [5,3,1,0.sup.2,6 ] undecane                                        ##STR78##         156-167                                   72   5-Methyl-1- azatricyclo [5,3,1,0.sup.2,6 ] undecane                                        ##STR79##         156-168                                   73   8-Methyl-1- azatricyclo [5,3,1,0.sup.2,6 ] undecane                                        ##STR80##         156-166                                   74   9-Methyl-1- azatricyclo  [5,3,1,0.sup.2,6 ] undecane                                       ##STR81##         156-167                                   75   10-Methyl-1- azatricyclo [5,3,1,0.sup.2,6 ] undecane                                       ##STR82##         155-166                                   76   1-Azatricyclo [6,3,1,0.sup.2,7 ] dodecane                                                  ##STR83##         154-166                                   77   1-Azatricyclo [6,3,1,0.sup.2,6 ] dodecane                                                  ##STR84##         155-166                                   78   1-Azatricyclo [6,3,1,0.sup.3,7 ] dodecane                                                  ##STR85##         155-166                                   79   1-Azatricyclo [7,3,1,0.sup.2,6 ] tridecane                                                 ##STR86##         167-177                                   80   1-Azatricyclo [7,3,1,0.sup.2,8 ] tridecane                                                 ##STR87##         167-177                                   81   1-Azatricyclo [7,3,1,0.sup.2,8 ] tridecane                                                 ##STR88##         167-177                                   82   1-Azatricyclo [7,3,1,0.sup.3,7 ] tridecane                                                 ##STR89##         166-176                                   83   1-Azatricyclo [7,3,1,0.sup.3,8 ] tridecane                                                 ##STR90##         167-177                                   84   1-Azatricyclo [7,3,1,0.sup.4,8 ] tridecane                                                 ##STR91##         167-177                                   85   1-Azatricyclo [5,4,1,0.sup.2,6 ] dodecane                                                  ##STR92##         155-166                                   86   1-Azatricyclo [6,4,1,0.sup.2,7 ] tridecane                                                 ##STR93##         167-178                                   87   1-Azatricyclo [6,4,1,0.sup.2,6 ] tridecane                                                 ##STR94##         167-177                                   88   1-Azatricyclo [6,4,1,0.sup.3,7 ] tridecane                                                 ##STR95##         167-177                                   89   1-Azatricyclo [5,2,2,0.sup.2,6 ] undecane                                                  ##STR96##         144-155                                   90   3-Methyl-1- azatricyclo [5,2,2,0.sup.2,6 ] undecane                                        ##STR97##         156-167                                   91   4-Methyl-1- azatricyclo [5,2,2,0.sup.2,6 ] undecane                                        ##STR98##         155-166                                   92   5-Methyl-1- azatricyclo [5,2,2,0.sup.2,6 ] undecane                                        ##STR99##         156-167                                   93   8-Methyl-1- azatricyclo [5,2,2,0.sup.2,6 ] undecane                                        ##STR100##        156-166                                   94   9-Methyl-1- azatricyclo  [5,2,2,0.sup.2,6 ] undecane                                       ##STR101##        156-166                                   95   1-Azatricyclo [6,2,2,0.sup.2,7 ] dodecane                                                  ##STR102##        155-165                                   96   1-Azatricyclo [6,2,2,0.sup.2,6 ] dodecane                                                  ##STR103##        156-166                                   97   1-Azatricyclo [6,2,2,0.sup.3,7 ] dodecane                                                  ##STR104##        156-166                                   98   1-Azatricyclo [7,2,2,0.sup.2,6 ] tridecane                                                 ##STR105##        157-166                                   99   1-Azatricyclo [7,2,2,0.sup.2,7 ] tridecane                                                 ##STR106##        156-167                                   100  1-Azatricyclo [7,2,2,0.sup.2,8 ] tridecane                                                 ##STR107##        155-167                                   101  1-Azatricyclo [7,2,2,0.sup.3,7 ] tridecane                                                 ##STR108##        156-167                                   102  1-Azatricyclo [7,2,2,0.sup.3,8 ] tridecane                                                 ##STR109##        156-166                                   103  1-Azatricyclo [7,2,2,0.sup.4,8 ] tridecane                                                 ##STR110##        154-166                                   104  1-Azatricyclo [6,3,2,0.sup.2,6 ] tridecane                                                 ##STR111##        156-166                                   105  1-Azatricyclo [6,3,2,0.sup.2,7 ] tridecane                                                 ##STR112##        156-166                                   106  1-Azatricyclo [6,3,2,0.sup.3,7 ] tridecane                                                 ##STR113##        156-167                                   107   1-Azatricyclo [5,3,3,0.sup.2,6 ] tridecane                                                ##STR114##        155-165                                   ______________________________________                                    

What is claimed is:
 1. A perfluoro-1-azatricyclic amine compound of theformula: ##STR115## any carbon of the formula being optionallysubstituted with at least one trifluoromethyl group or onepentafluoroethyl group.
 2. A composition for use as a blood substituteor infusion fluid which composition is an aqueous emulsion of a compoundof the formula given and defined in claim
 1. 3. A composition accordingto claim 2, which contains from 5 to 50% (W/V) of the compound of theformula given and defined in claim
 1. 4. A composition according toclaim 2, which contains, as emulsifier, a nonionic surfactant and/orphospholipid.